Identification of 4-aminopyrazolylpyrimidines as potent inhibitors of Trk kinases

Journal of Medicinal Chemistry

Volumn 51, Issue 15, 2008, Pages 4672-4684

  Wang, Tao ^a   Lamb, Michelle L ^a   Scott, David A ^a   Wang, Haixia ^a   Block, Michael H ^a   Lyne, Paul D ^a   Lee, John W ^a   Davies, Audrey M ^a   Zhang, Hai Jun ^a   Zhu, Yanyi ^a   Gu, Fei ^a   Han, Yongxin ^b   Wang, Bin ^b   Mohr, Peter J ^b   Kaus, Robert J ^b   Josey, John A ^b   Hoffmann, Ethan ^a   Thress, Ken ^a   MacIntyre, Terry ^a   Wang, Haiyun ^a   Omer, Charles A ^a   Yu, Dingwei ^a   more..

^a ASTRAZENECA   (United Kingdom)

^b ARRAY BIOPHARMA INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 ((5 CHLORO 4 [(3 CYCLOPROPYL 1H PYRAZOL 5 YL)AMINO] 6 [(2 MORPHOLIN 4 YLETHYL)AMINO] PYRIMIDIN 2 YL)AMINO 2 (4 FLUOROPHENYL)ETHANOL; 2 [5 CHLORO 2 [[1 (5 FLUOROPYRIDIN 2 YL)ETHYL]AMINO] 6 [(5 PROPAN 2 YLOXY 1H PYRAZOL 3 YL)AMINO]PYRIMIDIN 4 YL]OXYPROPANE 1,3 DIOL; 2 [[5 BROMO 4 [(5 CYCLOPROPYL 2H PYRAZOL 3 YL)AMINO]PYRIMIDIN 2 YL]AMINO] 2 PHENYLETHANOL; 2 [[5 BROMO 4 [(5 CYCLOPROPYL 2H PYRAZOL 3 YL)AMINO]PYRIMIDIN 2 YL]AMINO]2 PHENYLETHANOL; 2 [[5 CHLORO 2 [[1 (4 FLUOROPHENYL)ETHYL]AMINO] 6 [(5 PROPAN 2 YLOXY 1H PYRAZOL 3 YL)AMINO]PYRIMIDIN 4 YL]AMINO]PROPANE 1,3 DIOL; 2 [[5 CHLORO 4 (2H PYRAZOL 3 YLAMINO)PYRIMIDIN 2 YL]AMINO] 2 (4 FLUOROPHENYL)ETHANOL; 2 [[5 CHLORO 4 [(5 CYCLOPROPYL 2H PYRAZOL 3 YL)AMINO]PYRIMIDIN 2 YL]AMINO] 2 (4 FLUOROPHENYL)ETHANOL; 2 [[5 CHLORO 4 [(5 METHYLSULFANYL 2H PYRAZOL 3 YL)AMINO]PYRIMIDIN 2 YL] 2 (4 FLUOROPHENYL)ETHANOL; 2 [[5 CHLORO 4 [(5 PROPOXY 2H PYRAZOL 3 YL)AMINO]PYRIMIDIN 2 YL]AMINO 2 (4 FLUOROPHENYL)ETHANOL; 2 [[5 CHLORO 6 [(5 CYCLOPROPYL 2H PYRAZOL 3 YL)AMINO] 2 [[1 (4 FLUOROPHENYL)ETHYL]AMINO]PYRIMIDIN 4 YL]AMINO]ETHANOL; 3 [[ CHLORO 4 [(5 CYCLOPROPYL 1H PYRAZOL 3 YL)AMINO]PYRIMIDIN 2 YL]AMINO] 3 (4 FLUOROPHENYL) N,N DIMETHYLPROPANAMIDE; 3 [[2 [[1 (4 FLUOROPHENYL)ETHYL]AMINO] 6 [(5 METHYL 1H PYRAZOL 3 YL)AMINO]PYRIMIDIN 4 YL]AMINO]PROPANE 1,2 DIOL; 3 [[5 CHLORO 6 [(5 CYCLOPROPYL 2H PYRAZOL 3 YL)AMINO] 2 [[1 (4 FLUOROPHENYL)ETHYL]AMINO]PYRIMIDIN 4 YL]AMINO]PROPANE 1,2 DIOL; 3 [[6 [(5 CYCLOPROPYL 1H PYRAZOL 3 YL)AMINO] 2 [[1 (4 FLUOROPHENYL)ETHYL]AMINO]PYRIMIDIN 4 YL]AMINO]PROPANE 1,2 DIOL; 5 BROMO N [(2 CHLOROPHENYL)METHYL] N' (5 CYCLOPROPYL 1H PYRAZOL 3 YL)PYRIMIDINE 2,4 DIAMINE; 5 BROMO N [(4 CHLOROPHENYL)METHYL] N' (5 CYCLOPROPYL 1H PYRAZOL 3 YL)PYRIMIDINE 2,4 DIAMINE; 5 BROMO N' (5 CYCLOPROPYL 1H PYRAZOL 3 YL) N [(2 METHOXYPHENYL)METHYL]PYRIMIDINE 2,4 DIAMINE; 5 BROMO N' (5 CYCLOPROPYL 1H PYRAZOL 3 YL) N [(3 METHOXYPHENYL)METHYL]PYRIMIDINE 2,4 DIAMINE; 5 BROMO N' (5 CYCLOPROPYL 1H PYRAZOL 3 YL) N [1 PHENYLETHYL]PYRIMIDINE 2,4 DIAMINE; 5 BROMO N' (5 CYCLOPROPYL 2H PYRAZOL 3 YL) N [(4 FLUOROPHENYL)METHYL]PYRIMIDINE 2,4 DIAMINE; 5 BROMO N' (5 CYCLOPROPYL 2H PYRAZOL 3 YL) N [1 (4 FLUOROPHENYL)ETHYL]PYRIMIDINE 2,4 DIAMINE; 5 CHLORO N 2 [ 1 (5 FLUOROPYRIDIN 2 YL)ETHYL] N 4 (5 ISOPROPOXY 1H PYRAZOL 3 YL)PYRAMIDINE 2,4 DIAMINE; 5 CHLORO N 4 (5 CYCLOPROPYL 1H PYRAZOL 3 YL) N 2 (1 ( 5 FLUOROPYRIDIN 2 YL)ETHYL)PYRIMIDINE 2,4 DIAMINE; 5 CHLORO N [1 (FLUOROPHENYL)ETHYL] N' (5 METHYL 1H PYRAZOL 3 YL)PYRIMIDINE 2,4 DIAMINE; 5 FLUORO N 4 (5 CYCLOPROPYL 1H PYRAZOL 3 YL) N 2 (1 (5 FLUOROPYRIDIN 2 YL)ETHYL)PYRIMIDINE 2,4 DIAMINE; N BENZYL 5 BROMO N' (5 CYCLOPROPYL 2H PYRAZOL 3 YL)PYRIMIDINE 2,4 DIAMINE; N' (5 TERT BUTYL 1H PYRAZOL 3 YL) 5 CHLORO N [1 (4 FLUOROPHENYL)ETHYL]PYRIMIDINE 2,4 DIAMINE; PROTEIN TYROSINE KINASE INHIBITOR; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG IDENTIFICATION; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; MALE; NONHUMAN; RAT;

AMINES; ANIMALS; CELL LINE; HUMANS; MALE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PYRAZOLES; PYRIMIDINES; RATS; RATS, WISTAR; RECEPTOR, TRKA; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 49449105822     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800343j     Document Type: Article

References (36)

1. Gschwind, A.; Fischer, O. M.; Ullrich, A. The Discovery of Receptor Tyrosine Kinases: Targets for Cancer Therapy. Nat. Rev. Cancer 2004, 4, 361-370.
2. Pattarawarapan, M.; Burgess, K. Molecular Basis of Neurotrophin-Receptor Interactions. J. Med. Chem. 2003, 46, 52775291.
3. Patapoutian, A.; Reichardt, L. F. Trk Receptors: Mediators of Neurotrophin Action. Curr. Opin. Neurobiol. 2001, 11, 272-280.
4. Pezet, S.; McMahon, S. B. Neurotrophins: Mediators and Modulators of Pain. Annu. Rev. Neurosci. 2006, 29, 507-538.
5. Weeraratna, A. T.; Arnold, J. T.; George, D. J.; DeMarzo, A.; Isaacs, J. T. Rational Basis for Trk Inhibition Therapy for Prostate Cancer. Prostate 2000, 45, 40-48.
6. Brodeur, G. M. Neuroblastoma: Biological Insights Into A Clinical Enigma. Nat. Rev. Cancer 2003, 3, 203-216.
7. Schramm, A.; Schulte, J. H.; Astrahantseff, K.; Apostolov, O.; Limpt, V. V.; Sieverts, H.; Kuhfittig-Kulle, S.; Pfeiffer, P.; Versteeg, R.; Eggert, A. Biological Effects of TrkA and TrkB Receptor Signaling in Neuroblastoma. Cancer Lett. 2005, 228, 143-153.
8. Izbicka, E.; Izbicki, T. Therapeutic Strategies for the Treatment of Neuroblastoma. Curr. Opin. Investig. Drugs 2005, 6, 1200-1214.
9. Tacconelli, A.; Farina, A. R.; Cappabianca, L.; DeSantis, G.; Tessitore, A.; Vetuschi, A.; Sferra, R.; Rucci, N.; Argenti, B.; Screpanti, I.; Gulino, A.; Mackay, A. R. TrkA Alternative Splicing: A Regulated Tumor-promoting Switch in Human Neuroblastoma. Cancer Cell 2004, 6, 347-360.
10. Davidson, B.; Reich, R.; Lazarovici, P.; Nesland, J. M.; Skrede, M.; Risberg, B.; Trope, C. G.; Flørenes, V. A. Expression and Activation of the Nerve Growth Factor Receptor TrkA in Serous Ovarian Carcinoma. Clin. Cancer Res. 2003, 9, 2248-2259.
11. Bardelli, A.; Parsons, D. W.; Silliman, N.; Ptak, J.; Szabo, S.; Saha, S.; Markowitz, S.; Willson, J. K. V.; Parmigiani, G.; Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. Mutational Analysis of the Tyrosine Kinome in Colorectal Cancers. Science 2003, 300, 949-949.
12. Marshall, J. L.; Kindler, H.; Deeken, J.; Bhargava, P.; Vogelzang, N. J.; Rizvi, N.; Luhtala, T.; Boylan, S.; Dordal, M.; Robertson, P.; Hawkins, M. J.; Ratain, M. J. Phase I Trial of Orally Administered CEP-701, a Novel Neurotrophin Receptor-linked Tyrosine Kinase Inhibitor. Investig. New Drugs 2005, 23, 31-37.
13. Fancelli, D.; Moll, J. R.; Varasi, M.; Bravo, R.; Artico, R.; Berta, D.; Bindi, S.; Cameron, A.; Candiani, I.; Cappella, P.; Carpinelli, P.; Croci, W.; Forte, B.; Giorgini, M. L.; Klapwijk, J.; Marsiglio, A.; Pesenti, E.; Rocchetti, M.; Roletto, F.; Severino, D.; Soncini, C.; Storici, P.; Tonani, R.; Zugnoni, P.; Vianello, P. 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazoles: Identification of a Potent Aurora Kinase Inhibitor with a Favorable Antitumor Kinase Inhibition Profile. J. Med. Chem. 2006, 49, 7247-7251.
14. Baker, D.; Tkalcevic, G.; Clark, T.; Patel, N.; Cohen, B.; LaGreca, S.; Kakar, S.; Vincent, P.; Martinez-Alsina, L.; Marx, M.; Arcar, J.; Lu, Y.; Chen, M.; Hungerford, W. Evaluation Of Antitumor, Anti-Angiogenic, And Biomarker Endpoints For Orally Active Tie-2 Kinase Inhibitors. AACR Annual Meeting Los Angeles, CA, April 14-18, 2007, Poster 2140.
15. Wood, E. R.; Kuyper, L.; Petrov, K. G.; Robert, N.; Hunter, I.; Harris, P. A.; Lackey, K. Discovery and in Vitro Evaluation of Potent TrkA Kinase Inhibitors: Oxindole and Aza-oxindoles. Bioorg. Med. Chem. Lett. 2004, 14, 953-957.
16. Lippa, B.; Morris, J.; Corbett, M.; Kwan, T. A.; Noe, M. C.; Snow, S. L.; Gant, T. G.; Mangiaracina, M.; Coffey, H. A.; Foster, B.; Knauth, E. A.; Wessel, M. D. Discovery of Novel Isothiazole Inhibitors of the TrkA Kinase: Structure-Activity Relationship, Computer Modeling, Optimization, and Identification of Highly Potent Antagonists. Bioorg. Med. Chem. Lett. 2006, 16, 3444-3448.
17. Kim, S.-H.; Tokarski, J. S.; Leavitt, K. J.; Fink, B. E.; Salvati, M. E.; Moquin, R.; Obermeier, M. T.; Trainor, G. L.; Vite, G. G.; Stadnick, L. K.; Lippy, J. S.; You, D.; Lorenzi, M. V.; Chen, P. Identification of 2-Amino-5-(thioaryl)thiazoles as Inhibitors of Nerve Growth Factor Receptor TrkA. Bioorg. Med. Chem. Lett. 2008, 18, 634-639.
18. Gaul, M. D.; Xu, G.; Baumann, C. A. Aminopyrimidines as Kinase Modulators. U.S. Appl. US2006281764, 2006.
19. Lee, W.; Ladouceur, G.; Dumas, J.; Smith, R.; Ying, S.; Wang, G.; Chen, Z.; Liu, Q.; Mokdad, H. H. Substituted Pyrazolyl Urea Derivatives Useful in the Treatment of Cancer. PCT Int. Appl., WO2005110994, 2005.
20. Tanaka, M.; Yuno, T.; Kitagawa, Y. Neurotrophin-inhibiting Condensed Pyrazoles and Analgesics Containing Them. Jpn. Kokai Tokkyo Koho JP2003231687, 2003.
21. Honma, T.; Yoshizumi, T.; Hashimoto, N.; Hayashi, K.; Kawanishi, N.; Fukasawa, K.; Takaki, T.; Ikeura, C.; Ikuta, M.; Suzuki-Takahashi, I.; Hayama, T.; Nishimura, S.; Morishima, H. A Novel Approach for the Development of Selective Cdk4 Inhibitors: Library Design Based on Locations of Cdk4 Specific Amino Acid Residues. J. Med. Chem. 2001, 44, 4628-4640.
22. Creemer, L. C.; Bargar, T. M.; Wagner, E. R. A Convenient Synthesis of Bis(alkylthio)Acrylonitriles. Synth. Commun. 1988, 18, 1103-1110.
23. Burk, M. J. Modular Phospholane Ligands in Asymmetric Catalysis. Acc. Chem. Res. 2000, 33, 363-372.
24. Angeles, T. S.; Lippy, J. S.; Yang, S. X. Quantitative, High-Throughput Cell-Based Assays for Inhibitors of TrkA Receptor. Anal. Biochem. 2000, 278, 93-98.
25. Reuther, G. W.; Lambert, Q. T.; Caligiuri, M. A.; Der, C. J. Identification and Characterization of an Activating TrkA Deletion Mutation in Acute Myeloid Leukemia. Mol. Cell. Biol. 2000, 20, 8655-8666.
26. Morgenthaler, M.; Schweizer, E.; Hoffmann-Roder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Muller, K. Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities. ChemMedChem 2007, 2, 1100-1115.
27. Thress, K.; Hoffmann, E.; MacIntyre, T.; Wang, H.; Whitston, D.; Liu, Z.-Y.; Wang, T.; Brown, J. L.; Webster, K.; Omer, C. Unpublished results.
28. Insight II Modeling Environment; Accelrys Software Inc.: San Diego, CA, 2002.
29. Hubbard, S. R. Crystal Structure of the Activated Insulin Receptor Tyrosine Kinase in Complex with Peptide Substrate and ATP Analog. EMBO J. 1997, 16, 5572-5581.
30. Mohammadi, M.; Schlessinger, J.; Hubbard, S. R. Structure of the FGF Receptor Tyrosine Kinase Domain Reveals a Novel Autoinhibitory Mechanism. Cell 1996, 86, 577-587.
31. Zhu, X.; Kim, J. L.; Newcomb, J. R.; Rose, P. E.; Stover, D. R.; Toledo, L. M.; Zhao, H.; Morgenstern, K. A. Structural Analysis of the Lymphocyte-Specific Kinase Lck in Complex with Nonselective and Src Family Selective Kinase Inhibitors. Structure 1999, 7, 651-661.
32. Xu, W.; Doshi, A.; Lei, M.; Eck, M. J.; Harrison, S. C. Crystal Structures of c-Src Reveal Features of Its Autoinhibitory Mechanism. Mol. Cell 1999, 3, 629-638.
33. Breault, G. A.; Ellston, R. P. A.; Green, S.; James, S. R.; Jewsbury, P. J.; Midgley, C. J.; Pauptit, R. A.; Minshull, C. A.; Tucker, J. A.; Pease, J. E. Cyclin-Dependent Kinase 4 Inhibitors as a Treatment for Cancer. Part 2: Identification and Optimization of Substituted 2,4-Bis Anilino Pyrimidines. Bioorg. Med. Chem. Lett. 2003, 13, 2961-2966.
34. Glide XP, 2.5 ed.; Schrödinger Inc.: New York, 2003.
35. Molecular Networks CORINA, 3.0 ed.; Gasteiger Research: Erlangen, Germany, 2003.
36. Gasteiger, J.; Rudolph, C.; Sadowski, J. Automatic Generation of 3D-atomic Coordinates for Organic Molecules. Tetrahedron Comput. Methods 1990, 3, 537-547.